Syphilis is a major public health problem in parts of the US and in the developing world. A vaccine to prevent syphilis is urgently needed. Treponema pallidum subsp. Pallidum, the spirochete that causes syphilis, has 12 polymorphic genes that encode proteins with homology to the major sheath protein (msp) of Treponema denticola. In preliminary experiments, immunization with T. p. pallidum. Nichols strain msp-homologue recombinant proteins was partially protective against challenge with T. p. pallidum Nichols strain. The overall goal of this research is to use msp-homologues to develop a protective vaccine against T. p. pallidum infection. The specific aims of this project are the following: 1. Test the ability of immunization with msp- homologues to protect the challenge with T.p. pallidum Nichols strain. This aim will test the hypothesis that immunizing with msp-homologues of T.p. pallidum Nichols strain will lead to protection against challenge with Nichols strain. Immunization using the variable and constant domains will be compared, as will immunization with multiple versus single msp homologues. 2. Determine the heterogeneity of msp-homologue genes in other strains of T.p. pallidum The RFLPs of the4 variable domains of msp- homologue genes are different from strain to strain. In this aim, the variable domains of different strains will be compared by sequence analysis. 3. Test the ability of immunization with msp-homologues to protect from infection with multiple strains of T.p. pallidum. We hypothesize that strain heterogeneity of msp-homologues explain the lack of cross-protection after infection with heterologous strains. The protective capacity of Nichols strain msp-homologues will be compared with heterologous and Nichols strain challenge. As the diversity of msp-homologues among the strains is understood, a multivalent immunization with msp-homologues will be devised to provide protection against challenge with multiple strains. 4. Test alterative vaccine strategies for protection against T.p. pallidum. This aim will test the hypothesis that delivery of msp-homologues via alternative strategies targeting mucosal and CD8/class I immunity will improve protection against challenge with T.p. pallidum. The results of these studies will lead to an understanding of the mechanisms of protective immunity in syphilis and ultimately lead to a vaccination strategy to prevent syphilis.